This is the largest retrospective cohort study of NCBE in Japan and serves as a benchmark for the epidemiological understanding of NCBE in Asia, shedding light on prognostic indicators. We found that the mortality rate was low and identified a significant prevalence of comorbidities, including NTM, prior TB, and sinusitis infections. Prognostic factors were similar to those from previous studies: higher BMI was associated with a lower risk of exacerbations and mortality, while factors such as COPD and disease severity on CT significantly increased risk, and NTM did not affect prognosis. Moreover, although many patients with non-NTM BE received long-term macrolide antibiotics, a significant proportion of these were patients without a history of exacerbations. This treatment did not significantly affect the time to the first severe exacerbation post-diagnosis in patients with non-NTM BE.
Regarding patient characteristics, our population had more older patients, women, patients with lower BMI, and never-smokers than those in the EMBARC registry data [3]. Although the incidence of severe exacerbations aligns with previously reported data, our 1- and 3-year mortality rates were notably lower (Table 1). These gaps may be due to capturing milder cases by the widespread availability of CT, variations in insurance coverage, differing criteria for hospitalization, and prevalence of the screening system [20–23].
Our study did not aim to identify specific etiologies but to document the frequency of comorbidities that can lead to this condition, emphasizing their prevalence. The significant co-occurrence of NTM aligns with the findings of previous research [4].
The frequency of idiopathic and post-infection BE cases was similar to that reported in previous studies [5, 24]. However, a predominance of older patients with TB was observed (n = 100). Logistic regression analysis revealed a significant correlation between age and TB (p < 0·0001) (data not shown). These findings may represent subsets that are particularly prevalent in Asia populations.
Numerous patients within the cohort were categorized as having severe disease based on the BSI score, a classification that appears incongruent with the observed mortality rates. In the Japanese context, factors such as older age and physically lower BMI may contribute to elevated BSI scores (Table 1). These scores may not provide clinicians with insight into the specific management strategies required in routine clinical practice [25].
Determining whether NTM infection precedes the development of BE remains challenging [16]. However, similar to that reported in recent U.S. cohorts [26], many NCBE patients met the American Thoracic Society/Infectious Diseases Society of America criteria for NTM pulmonary disease. The 5-year mortality rate was low, and survival outcomes did not differ significantly between patients with and without NTM, aligning with findings from the U.S. registry. Our validation reaffirms the high prevalence of NTM in Japan and represents Asia and Japanese landscape.
When focusing on the differences between the non-NTM and NTM groups, we found that the non-NTM group had a significantly higher proportion of men and elevated BMI and inflammatory markers, such as BNCs, CRP, and ESR. Previous large-scale database and cohort analyses have not reported data specifically focusing on this inflammatory profile [11, 27, 28]. In future studies, it may be crucial to categorize patients with NCBE based on their endotypes and phenotype [29] for precision medicine.
Regarding the results for each prognostic indicator utilized in daily practice, COPD, inflammatory markers such as CRP, cavities, and cystic bronchiectasis were associated with mortality and severe exacerbation, similar to previous reports [22, 30–33] (Figs. 2a, 2b, and 3b). Notably, in patients without NTM, inflammation may play a crucial role in exacerbation (Table 2 and Fig. 2a), highlighting the pathophysiological vortex of disease progression [1, 15, 34, 35]. Therefore, these results suggest the need to manage the inflammatory process [35].
In contrast, P. aeruginosa is a well-established prognostic factor for bronchiectasis [18]; however, in our study, it was more frequently identified as a colonizing or pathogenic microorganism with severe exacerbations in the non-NTM group but not in the NTM group (Table 2 and Supplementary Table S1 [see Additional file 1]). Additionally, in a recent U.S. study focusing on the presence or absence of NTM in the BE registry, P. aeruginosa was not identified as a prognostic factor [26]. This raises questions about whether differences exist in prognostic factors between patients with and without NTM. One study indicated that bacterial coinfections can occur after starting treatment for Mycobacterium avium complex pulmonary disease [36]. Under certain conditions, NTM might provide a protective effect against Pseudomonas infection, or they may regulate each other’s virulence. These findings suggest complex interactions within the bacterial flora that warrant further investigation.
We focused on the prescription pattern in patients without NTM infection. Compared with Western registries such as EMBARC [3], this cohort showed higher use of macrolides and lower use of inhaled steroids and inhaled antibiotics. In Japan, macrolide antibiotics are indicated for neutrophilic airway inflammation and can be used in a wide range of conditions, including COPD, DPB, bronchiectasis, and bronchial asthma, with or without a history of exacerbations. However, the indiscriminate use of macrolides contributes to increased resistance in potentially co-existing NTM. Additionally, the use of inhaled corticosteroids (ICSs) in this cohort was primarily noted in cases with coexisting asthma, highlighting regional differences in treatment practices; in Western countries, ICSs are more commonly prescribed directly for bronchiectasis. In Japan, inhaled tobramycin is only approved for CF, and amikacin liposomal inhalation is only approved for treatment-resistant Mycobacterium avium complex, reflecting further limitations in treatment options for BE. We also found substantial prescription of clarithromycin monotherapy for milder cases. Moreover, very few instances of erythromycin or azithromycin use have been observed. These behaviors may not reflect widely recognized guidelines (Supplementary Table S4 [see Additional file 1]) [8, 9]. The results of our covariate-adjusted IPW analysis suggested that the prophylactic use of long-term macrolide antibiotics did not invariably reduce further severe exacerbations in patients with no history of such events (Fig. 4a, b). We speculate that there is high awareness and active research on DPB in Japan [7]. NCBE has long been considered an orphan disease [2]. Furthermore, successful experiences with macrolides in DPB [7] may have led to a dependency on these medications. Additionally, the lack of inhaled antibiotic options for non-CF BE in Japan may have contributed to this dependency.
Our findings serve as a cautionary note for routine clinical practice in Japan. The unrestricted prescription of macrolides can lead to refractoriness and resistance in NTM. Further verification of the effectiveness of macrolides in mild cases is required, not only in suppressing exacerbations but also in improving symptoms, quality of life, and effects on comorbid chronic sinusitis.
In summary, this cohort study clarified the epidemiology of NCBE and the potential parameters that guide patient management in Japan. Moreover, our findings critically verify the application of macrolides in routine clinical settings and underscore the need for further investigation in this field.
This study had some limitations. First, its retrospective design precluded elimination of all potential confounding factors. Although substantial cohorts exist globally, the evidence is particularly sparse in Japan, underscoring the necessity for ongoing real-world cohort studies in future. Second, there was a lack of PFT data. In a Cox proportional hazard regression for multivariate analysis, a variable with missing data was not suitable for evaluation as a prognostic value, and we did not consider PFTs or each severity index as prognostic variables. This study highlights the need to increase our awareness and understanding of BE, perform PFTs, and regularly follow-up in daily clinical practice. Third, the lack of a validation cohort within our study precluded the verification of predictive accuracy. However, our primary goal was not to construct a prediction model but to provide the first epidemiological overview relevant to Japan and Asia. Further research is needed to identify predictors of poor outcomes. Fourth, the retrospective nature of the study also means that treatment decisions regarding the timing and choice of macrolide antibiotics were at the discretion of individual pulmonary physicians, introducing the potential for immortal time bias in assessing the ATE of long-term macrolide antibiotics. Future randomized controlled trials in patient populations with no previous exacerbations are needed for an accurate evaluation. Fifth, the end point of follow-up termination may have introduced a measurement bias affecting the interpretation of the results. Efforts have been made to mitigate this through extensive follow-up via regional medical liaison offices and interhospital communication, minimizing loss to death or follow-up discontinuation. Sixth, this study does not identify the specific etiology of bronchiectasis because bronchiectasis can have multiple potential causes, making it impossible to pinpoint a single etiology. Seventh, approximately 23% of patients without NTM tested positive for IgA antibodies to glycopeptidolipid core antigen, suggesting that NTM might be underestimated. Hence, it is challenging to capture the true NTM population.